Retacrit (epoetin alfa-epbx)

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Administer epoetin alfa products by IV or subcutaneous injection. In patients undergoing hemodialysis, the manufacturers recommend that epoetin alfa products be given IV rather than subcutaneously because of reports of pure red cell aplasia (PRCA) associated with the latter route of administration.

Do not shake or freeze vials of epoetin alfa product, and discard if subjected to these conditions.

Inspect visually the contents of vials of epoetin alfa product for discoloration and/or particulate matter prior to administration whenever solution and container permit; if either is present, discard the solution.

For IV or subcutaneous use, withdraw the appropriate dose of the epoetin alfa product from the vial into the syringe for administration; once the dose has been withdrawn from the vial, administer promptly.

Do not mix epoetin alfa products with other drug solutions in general. However, the manufacturers of Epogen(R) and Procrit(R) state that the preservative-free formulation from single-use vials may be admixed in equal parts (in a 1:1 ratio) in a syringe with bacteriostatic 0.9% sodium chloride injection (preserved with benzyl alcohol) at the time of administration.

Discard unused portions of epoetin alfa product from single-dose preservative-free vials. Any unused portion of epoetin alfa product from multi-dose vials can be stored, protected from light, between 2-8degreesC for 21 days after initial entry. Because of the risks associated with benzyl alcohol, do not use epoetin alfa product that has been admixed with injection solutions containing benzyl alcohol in neonates, infants, and pregnant and nursing women.

No dosing information is available for this tab.

No dosing information is available for this tab.

Interactions between epoetin alfa and other drugs have not been fully evaluated.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Erythropoietic Agents/Lovotibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Erythropoietic agents may interfere with hematopoietic stem cell (HSC) mobilization of CD34+ cells.(1)

CLINICAL EFFECTS: Use of erythropoietic agents before mobilization may result in unsuccessful stem cell mobilization.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue erythropoietic agents at least 2 months prior to mobilization.(1)

DISCUSSION: Erythropoietic agents may interfere with the manufacturing of lovotibeglogene autotemcel therapy. There are no data regarding use of erythropoietin between apheresis and conditioning or after lovotibeglogene autotemcel therapy.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Erythropoietic Agents/Lenalidomide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of this interaction is unknown.

CLINICAL EFFECTS: Concurrent use of erythropoietic agents, such as darbepoetin or epoetin, with lenalidomide may increase the risk of thrombosis.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lenalidomide states the risk of venous thromboembolism (VTE) may be increased when patients are taking concomitant therapy with erythropoietin stimulating agents. Use caution with concomitant use after a patient specific risk-benefit assessment has been completed. Observe patients for signs and symptoms of VTE and instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.(1) The National Comprehensive Cancer Network (NCCN) Guidelines include use of erythropoietic stimulating agents as a high risk factor for venous thromboembolism (VTE). Other risk factors include: active cancer, advanced stage cancer, certain cancer types, regional bulky lymphadenopathy, familial and/or acquired hypercoagulability, medical comorbidities, poor performance status, older age, major surgery, central venous catheter, chemotherapy including lenalidomide plus high-dose dexamethasone, hormone replacement therapy, contraceptives, tamoxifen/raloxifene, diethylstilbestrol, smoking, obesity, or activity level/exercise.(3) The NCCN Guidelines utilize a Risk Assessment Model to determine chemoprophylaxis. In patients with 0-1 risk factors, consider VTE chemoprophylaxis with aspirin 81-325 mg once daily. In patients with >/= 2 risk factors, consider VTE chemoprophylaxis with low-molecular weight heparin (LMWH) with a dose equivalent to enoxaparin 40 mg once daily or full-dose warfarin with a dose to maintain a target international normalized ratio (INR) 2-3.(3)

DISCUSSION: The National Comprehensive Cancer Network (NCCN) Guidelines include use of erythropoietin as an individual risk factor for venous thromboembolism (VTE). Patients should be assessed for total risk based on NCCN guidelines and recommended for the appropriate VTE chemoprophylaxis agent based on risk category.(3) A pooled analysis of two placebo-controlled trials in multiple myeloma noted an incidence rate for VTE of 23% in patients receiving lenalidomide, dexamethasone and erythropoietic therapy versus 5% in patients without erythropoietic therapy. A multivariate analysis indicated an independent correlation between thrombosis and patients with concomitant erythropoietin therapy.(4) A pooled analysis of 125 patients from 3 trials with multiple myeloma on lenalidomide therapy noted a 17% incidence of VTE in patients on lenalidomide with concurrent erythropoietin therapy.(5) Several studies have evaluated the optimal VTE prophylaxis agent with lenalidomide-treated patients. Patients receiving lenalidomide/dexamethasone and no chemoprophylaxis had a VTE incidence of 11-75%, 26% with the use of aspirin, 17% with the use of aspirin/LMWH/warfarin combination therapy, and 2-15% with the use of LMWH. (6)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Erythropoietin Stimulating Agents/Vadadustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vadadustat and erythropoietin stimulating agents (ESAs) both stimulate endogenous erythropoietin production, resulting in increased red blood cell production.(1-2)

CLINICAL EFFECTS: Concurrent use of vadadustat and erythropoietin stimulating agents may increase the risk of thrombosis.

PREDISPOSING FACTORS: Predisposing factors include a history of thromboembolic disorder, thrombophilia, malignancy, hyperlipidemia, hypertension, heart failure, diabetes mellitus, chronic kidney disease, COPD, obesity, tobacco smoking, major surgery with prolonged post-operative immobilization, and being bed-ridden.

PATIENT MANAGEMENT: ESAs should be stopped before initiating vadadustat.(1) For patients receiving temporary ESA rescue treatment, vadadustat should be held until hemoglobin levels are greater than or equal to 10 g/dL. The pause in vadadustat treatment should be extended to: - 2 days after last dose of epoetin - 7 days after last dose of darbepoetin alfa - 14 days after last dose of methoxy polyethylene glycol-epoetin beta Vadadustat should be resumed at the prior dose or one dose higher, with subsequent titration according to the dose titration guidelines in the vadadustat package insert.(1-2) Monitor hemoglobin levels every two weeks until stable, then monitor at least monthly.(1-2) Observe patients for signs and symptoms of venous thromboembolism and instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.

DISCUSSION: Vadadustat increases endogenous erythropoietin by decreasing degradation of hypoxia-inducible factor (HIF), which increases transcription of the HIF-responsive genes including EPO. Thromboembolic events were reported as very common (13.7%) in two active-controlled clinical trials in chronic kidney disease.(1-2) Controlled clinical trials of patients showed that ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, and other thromboembolic events with a higher target hemoglobin.(3)

*Uncontrolled hypertension.

*Pure red cell aplasia (PRCA) following treatment with epoetin alfa products or other erythropoietin proteins.

*History of a serious allergic reaction to epoetin alfa products.

*Use of epoetin alfa products from multi-dose vials containing benzyl alcohol in women who are pregnant or breastfeeding, neonates, and infants.

• Pure red cell aplasia
• Severe uncontrolled hypertension

• Acute decompensated heart failure
• Acute myocardial infarction
• Cerebrovascular accident
• Coronary artery disease
• Deep venous thrombosis
• Phenylketonuria
• Pulmonary thromboembolism
• Thromboembolic disorder
• Vascular access thrombosis

• Hypertension
• Iron deficiency anemia
• Seizure disorder

Patients with CKD (>=5%): hypertension, arthralgia, muscle spasm, pyrexia, dizziness, medical device malfunction, vascular occlusion, and upper respiratory tract infection.

Patients with HIV infection treated with zidovudine (>=5%): pyrexia, cough, rash, and injection site irritation.

Patients with cancer receiving chemotherapy (>=5%): nausea, vomiting, myalgia, arthralgia, stomatitis, cough, weight decrease, leukopenia, bone pain, rash, hyperglycemia, insomnia, headache, depression, dysphagia, hypokalemia, and thrombosis.

Surgical patients (>=5%): nausea, vomiting, pruritus, headache, injection site pain, chills, deep vein thrombosis, cough, and hypertension.

More Frequent

• Edema
• Hypertension
• Tachycardia
• Vascular access thrombosis

Less Frequent

• Acute myocardial infarction
• Cerebrovascular accident
• Headache disorder
• Hypokalemia
• Pulmonary thromboembolism
• Seizure disorder
• Thrombotic disorder
• Transient cerebral ischemia

Rare or Very Rare

• Anaphylaxis
• Angioedema
• Chest pain
• Chronic heart failure
• Deep venous thrombosis
• Erythema multiforme
• Porphyria
• Pure red cell aplasia
• Shortened time to tumor progression
• Stevens-johnson syndrome
• Thromboembolic disorder
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Anorexia
• Arthralgia
• Cough
• Diarrhea
• Fatigue
• Fever
• General weakness
• Injection site sequelae
• Insomnia
• Leukopenia
• Muscle spasm
• Nausea
• Vomiting

Less Frequent

• Bone pain
• Depression
• Dizziness
• Dysphagia
• Hyperglycemia
• Myalgia
• Stomatitis
• Upper respiratory infection

Rare or Very Rare

• Chills
• Flu-like symptoms
• Hyperhidrosis
• Skin rash

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The safety and efficacy of epoetin alfa products for the treatment of anemia associated with CKD, regardless of dialysis status, in pediatric patients younger than 1 month of age have not been established. In children at least 1 month of age with CKD, the pattern of most adverse events was similar to that found in adults. There does not appear to be a difference in safety profiles in pediatric patients with CKD requiring dialysis and not requiring dialysis.

The safety and efficacy of epoetin alfa products have not been established in pediatric patients who are younger than 5 years of age with cancer and receiving chemotherapy. In pediatric patients with cancer who are at least 5 years of age, the pattern of most adverse events was similar to that found in adults.

The safety and efficacy of epoetin alfa products have not been established in pediatric patients who are younger than 8 months of age with HIV infection receiving zidovudine.

Because of a potential risk of neurologic and other toxicity in neonates and infants exposed to benzyl alcohol, epoetin alfa products from multidose vials (with benzyl alcohol preservative) or from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol should not be used in these populations. When epoetin alfa products are needed for neonates or infants, use of a benzyl alcohol-free formulation is recommended.

Although there are no adequate and controlled studies to date of epoetin alfa product use during pregnancy, the drug has been used in a limited number of pregnant women with anemia alone or anemia associated with severe renal disease and hematologic disorders. Adverse pregnancy outcomes, including prenatal complications (i.e., polyhydramnios, intrauterine growth restriction) have been reported. The manufacturers state that due to the limited number of exposed pregnancies and the presence of multiple confounding factors (e.g., concomitant medications or other maternal conditions), such data cannot be used to reliably estimate the frequency or absence of adverse pregnancy outcomes. Epoetin alfa products should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Because of a potential risk of neurologic and other toxicity (e.g., gasping syndrome) in neonates exposed to benzyl alcohol, epoetin alfa product from multidose vials (with benzyl alcohol preservative) or from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol should not be used in pregnant women. When therapy is needed during pregnancy or nursing, use of a benzyl alcohol-free formulation is recommended.

It is not known whether epoetin alfa is distributed into human milk. The effects of the drug on breast-fed infants or on the production of milk are unknown. Because of the potential for adverse reactions to epoetin alfa in breast-fed infants, caution is advised in women who breast-feed while receiving the drug.

Because of a potential risk of neurologic and other toxicity in neonates exposed to benzyl alcohol, epoetin alfa from multidose vials (with benzyl alcohol preservative) or from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol should not be used in nursing women. The manufacturer advises women not to breastfeed for at least 2 weeks after the last dose of epoetin alfa product from a multidose vial. When therapy is needed for women who are nursing, use of a benzyl alcohol-free formulation is recommended.

In geriatric patients with anemia due to CKD, individualized dosing is recommended to maintain target hemoglobin concentrations.

The manufacturers of epoetin alfa products do not make specific dosage recommendations for geriatric patients with anemia and HIV infection treated with zidovudine.

In geriatric patients with chemotherapy-induced anemia and those undergoing elective surgery, dosage requirements appear to be similar to those in younger adults.

While safety and efficacy of epoetin alfa products have not been established specifically in geriatric patients, a large proportion of patients treated with the drug for anemia associated with CKD have been 65 years of age or older. In geriatric patients with anemia associated with CKD, no overall differences in safety and efficacy have been observed relative to younger adults.

In geriatric patients with anemia due to concomitant chemotherapy or in those undergoing elective surgery, no overall differences in safety and efficacy of epoetin alfa products have been observed relative to younger adults; dosing requirements generally were similar between geriatric patients and younger adults for each indication.

Data are insufficient in patients 65 years of age and older who have HIV infection and are treated with zidovudine to determine whether they respond differently than younger adults to epoetin alfa products.